Drugs that are effective in treating a number of psychiatric disorders appear to produce their effects by altering serotonin (5-HT) neurotransmission. The objective of this proposal is to examine the modulatory effects of the 5-HT 1A and 5-HT 1B receptors on the release of 5-HT in response to antidepressant drugs through the study of mutant mice with a constitutive deletion of either the 5-HT 1A or 5-HT 1B receptor. With either one of the presynaptic autoreceptors deleted, pharmacological challenges that increase the release of 5-HT (e.g., SSRIs) should demonstrate augmented effects on 5-HT release. Additionally, because both 5-HT 1A and 5-HT 1B receptors are involved in the presynaptic modulation of 5-HT release, they could potentially be part of compensatory mechanisms that develop when one of the receptors is deleted. These hypotheses will be assessed in several different studies. The effects of the novel 5-HT 1A receptor agonist 8-OH-PIPAT and the novel 5-HT 1B receptor agonist CP 94,253 on 5-HT release will be assessed in wild type mice. Both of these drugs shown distinct advantages over previously used drugs in pilot studies. Appropriate challenge conditions will be established. The effects of fluoxetine will then be assessed in 5-HT 1A and 5-HT 1B receptor knockout mice. These effects will subsequently be challenged by either a selective 5-HT 1A or 5-HT 1B receptor antagonist to assess the contributions to fluoxetine's effects of the 5-HT 1A receptor in 5-HT 1B receptor knockout mice and the 5-HT 1B receptor in 5-HT 1A receptor knockout mice. In mice with a constitutive deletion either of these autoreceptors, it is conceivable that the remaining autoreceptor may be involved in compensating for this specific loss of function. This hypothesis will be evaluated through pharmacological challenge of the 5-HT 1A receptor in the 5-HT 1B receptor knockout mice and the 5-HT 1B receptor in the 5-HT 1A receptor knockout mice under conditions developed above. In addition, pilot studies have shown a potentiated hypothermic response to 8-OH-DPAT, a 5-HT 1A receptor agonist, in 5-HT 1B receptor knockout animals. This effect will be assessed as a complementary physiological response that is sensitive to activation of distinct receptor subtypes. Finally, quantitative receptor auto- radiography will evaluate the quantity of 5-HT 1A and 5-HT 1B receptors in these mice. A greater understanding of the modulatory effects of the 5-HT 1A and 5-HT 1B receptors on the release of serotonin through their genetic deletion could lead to a better understanding of genetic contributions to differing sensitivities of humans to antidepressant treatment.